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Article: Bradykinin and high glucose promote renal tubular inflammation
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TitleBradykinin and high glucose promote renal tubular inflammation
 
AuthorsTang, SCW1
Chan, LYY1
Leung, JCK1
Cheng, AS1
Chan, KW1
Lan, HY1
Lai, KN1
 
KeywordsBradykinin
Chemokines
Diabetic nephropathy
High glucose
Kallirein
 
Issue Date2010
 
PublisherOxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/
 
CitationNephrology Dialysis Transplantation, 2010, v. 25 n. 3, p. 698-710 [How to Cite?]
DOI: http://dx.doi.org/10.1093/ndt/gfp599
 
AbstractBackground. The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.Methods and Results. High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF) and B2K receptor (B2KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-β mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-β, whereas inhibition of PKC by staurosporine partially reduced HG-but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-β expression. The B2KR blocker, icatibant, downregulated BK-and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG-and BK-induced IL-6, CCL-2 and TGF-β secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, attenuated HG-induced PKC but not HG-or BK-induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-β secretion. Rosiglitazone plus icatibant further reduced these effects of HG.Conclusions. In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B2KR blockade and PPAR-γ activation deserves clinical investigation.
 
ISSN0931-0509
2012 Impact Factor: 3.371
2012 SCImago Journal Rankings: 1.426
 
DOIhttp://dx.doi.org/10.1093/ndt/gfp599
 
ISI Accession Number IDWOS:000274987800012
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 7764/07M
Funding Information:

This work was supported by the Research Grants Council (General Research Fund ref HKU 7764/07M) of Hong Kong. Part of the data contained in this study was presented in abstract form at the American Society of Nephrology Annual Meeting and Scientific Exposition, November 6-9, 2008, Philadelphia, PA, USA. Icatibant was a kind gift from Sanofi-Aventis Deutschland GmbH. Rosiglitazone was a kind gift from GlaxoSmithKline (Compound Management Division, Stevenage, Herts, UK).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorTang, SCW
 
dc.contributor.authorChan, LYY
 
dc.contributor.authorLeung, JCK
 
dc.contributor.authorCheng, AS
 
dc.contributor.authorChan, KW
 
dc.contributor.authorLan, HY
 
dc.contributor.authorLai, KN
 
dc.date.accessioned2010-08-12T04:36:57Z
 
dc.date.available2010-08-12T04:36:57Z
 
dc.date.issued2010
 
dc.description.abstractBackground. The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.Methods and Results. High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF) and B2K receptor (B2KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-β mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-β, whereas inhibition of PKC by staurosporine partially reduced HG-but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-β expression. The B2KR blocker, icatibant, downregulated BK-and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG-and BK-induced IL-6, CCL-2 and TGF-β secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, rosiglitazone, attenuated HG-induced PKC but not HG-or BK-induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-β secretion. Rosiglitazone plus icatibant further reduced these effects of HG.Conclusions. In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B2KR blockade and PPAR-γ activation deserves clinical investigation.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationNephrology Dialysis Transplantation, 2010, v. 25 n. 3, p. 698-710 [How to Cite?]
DOI: http://dx.doi.org/10.1093/ndt/gfp599
 
dc.identifier.citeulike6185871
 
dc.identifier.doihttp://dx.doi.org/10.1093/ndt/gfp599
 
dc.identifier.epage710
 
dc.identifier.hkuros174356
 
dc.identifier.isiWOS:000274987800012
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 7764/07M
Funding Information:

This work was supported by the Research Grants Council (General Research Fund ref HKU 7764/07M) of Hong Kong. Part of the data contained in this study was presented in abstract form at the American Society of Nephrology Annual Meeting and Scientific Exposition, November 6-9, 2008, Philadelphia, PA, USA. Icatibant was a kind gift from Sanofi-Aventis Deutschland GmbH. Rosiglitazone was a kind gift from GlaxoSmithKline (Compound Management Division, Stevenage, Herts, UK).

 
dc.identifier.issn0931-0509
2012 Impact Factor: 3.371
2012 SCImago Journal Rankings: 1.426
 
dc.identifier.issue3
 
dc.identifier.openurl
 
dc.identifier.pmid19923143
 
dc.identifier.scopuseid_2-s2.0-77649226697
 
dc.identifier.spage698
 
dc.identifier.urihttp://hdl.handle.net/10722/65486
 
dc.identifier.volume25
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://ndt.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofNephrology Dialysis Transplantation
 
dc.relation.referencesReferences in Scopus
 
dc.rightsNephrology, Dialysis, Transplantation. Copyright © Oxford University Press.
 
dc.rightsThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nephrology, Dialysis, Transplantation following peer review.
 
dc.subject.meshBradykinin - physiology
 
dc.subject.meshDiabetic Nephropathies - pathology - physiopathology
 
dc.subject.meshGlucose - physiology
 
dc.subject.meshHyperglycemia - physiopathology
 
dc.subject.meshKidney Tubules, Proximal - pathology - physiopathology
 
dc.subjectBradykinin
 
dc.subjectChemokines
 
dc.subjectDiabetic nephropathy
 
dc.subjectHigh glucose
 
dc.subjectKallirein
 
dc.titleBradykinin and high glucose promote renal tubular inflammation
 
dc.typeArticle
 
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<contributor.author>Leung, JCK</contributor.author>
<contributor.author>Cheng, AS</contributor.author>
<contributor.author>Chan, KW</contributor.author>
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<description.abstract>Background. The role of the kallikrein-kinin system in diabetic nephropathy remains controversial.Methods and Results. High-glucose (HG) super-induced interleukin (IL)-6, CCL-2, transforming growth factor (TGF)-&#946;, vascular endothelial growth factor (VEGF) and B2K receptor (B2KR) mRNA in cultured proximal tubular epithelial cells (PTEC), whereas bradykinin (BK) upregulated IL-6, CCL-2 and TGF-&#946; mRNA. HG activated mitogen-activated protein kinase (MAPK) p42/p44 and protein kinase C (PKC) signals, whereas BK only activated MAPK. Tubular expression of these mediators and tissue kallikrein 1 (KLK1) was confirmed in human diabetic kidney biopsies. Inhibition of MAPK p42/p44 by PD98059 partially reduced HG and BK induction of IL-6, CCL-2 and TGF-&#946;, whereas inhibition of PKC by staurosporine partially reduced HG-but not BK-induced overexpression of these cytokines and that of VEGF. Staurosporine and PD98059 synergistically reduced the effect of HG on IL-6, CCL-2 and TGF-&#946; expression. The B2KR blocker, icatibant, downregulated BK-and HG-induced MAPK p42/p44 but not HG-induced PKC activation and partially reduced both HG-and BK-induced IL-6, CCL-2 and TGF-&#946; secretion. HG stimulated expression of KLK1 and low-molecular-weight kininogen (LMWK) and its downstream effects were attenuated by aprotinin (tissue kallikrein inhibitor). The peroxisome proliferator-activated receptor-&#947; (PPAR-&#947;) agonist, rosiglitazone, attenuated HG-induced PKC but not HG-or BK-induced MAPK p42/44 activation and reduced HG-stimulated VEGF, along with IL-6, CCL-2 and TGF-&#946; secretion. Rosiglitazone plus icatibant further reduced these effects of HG.Conclusions. In conclusion, HG stimulates tubular proinflammatory, profibrotic and angiogenic signals, which is partly mediated through BK via MAPK signalling and partly through PKC independent of BK. The potential therapeutic role of complementary B2KR blockade and PPAR-&#947; activation deserves clinical investigation.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong